Opposite change with ischaemia in the antifibrillatory effects of class I and class IV antiarrhythmic drugs resulting from the alteration in ion transmembrane exchanges related to depolarization

It is known that class I antiarrhythmic drugs lose their antifibrillatory a ctivity with severe ischaemia, whereas class IV antiarrhythmic drugs acquir e such activity. Tachycardia, which is also a depolarizing factor, has rece ntly been shown to give rise to an alteration of ion transmembrane exchange s which is particularly marked in the case of calcium. This leads one to wo nder if the change in antifibrillatory activity of antiarrhythmic drugs cau sed by ischaemia depends on the same process. The change in antifibrillator y activity was studied in normal conditions ranging to those of severe isch aemia with a class I antiarrhythmic drug, flecainide (1.00 mg.kg(-1) plus 0 .04 mg.kg(-1).min(-1)), a sodium channel blocker, and a class IV antiarrhyt hmic drug, verapamil (50 mu g.kg(-1) plus 2 mu g.kg(-1).min(-1)), a calcium channel blocker. The experiments were performed in anaesthetized, open-che st pigs. The resulting blockade of each of these channels was assessed at t he end of ischaemic periods of increasing duration (30, 60, 120, 180, 300, and 420 s) by determining the ventricular fibrillation threshold (VFT). VFT was determined by means of trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode introduced into the myocardium (hear t rate 180 beats per min). Ischaemia was induced by completely occluding th e left anterior descending coronary artery. The monophasic action potential was recorded concurrently for the measurement of ventricular conduction ti me (VCT). The monophasic action potential duration (MAPD) varied with membr ane polarization of the fibres. The blockade of sodium channels by flecaini de, which normally raises VFT (7.0 +/- 0.4 to 13.8 +/- 0.8 mA, p < 0.001) a nd lengthens VCT (28 +/- 3 to 44 +/- 5 ms, p < 0.001), lost its effects in the course of ischaemia. This resulted in decreased counteraction of the is chaemia-induced fall of VFT and decreased aggravation of the ischaemia-indu ced lengthening of VCT. The blockade of calcium channels, which normally do es not alter VFT (between 7.2 +/- 0.6 and 8.4 +/- 0.7 mA, n.s.) or VCT (bet ween 30 +/- 2 and 34 +/- 3 ms, n.s.), slowed the ischaemia-induced fall of VFT. VFT required more time to reach 0 mA, thus delaying the onset of fibri llation. Membrane depolarization itself was opposed as the shortening of MA PD and the lengthening of VCT were also delayed. Consequently there is a pr ogressive decrease in the role played by sodium channels during ischaemia i n the rhythmic systolic depolarization of the ventricular fibres. This redu ces or suppresses the ability of sodium channel blockers to act on excitabi lity or conduction, and increases the role of calcium channel blockers in a ttenuating ischaemia-induced disorders.